tbuckley/cabot-search huggingface dataset:
Biomarker Exploration for neoadjuvant chemotherapy with gemcitabine combined with cisplatin in muscle-invasive bladder cancer.
Authors: Kun Wang, Xusheng Chen, Zhenting Zhang, Hailong Hu, Aili Zhang, Xin Wang, Lijun Chen, Zhizhong Liu, Changjiu Yue, Xueying Zhang, Menghuan Zhang, Xin Yao
Journal: Journal of Clinical Oncology (2022)

e16556 Background: Neoadjuvant chemotherapy (NCT) is a standard treatment for muscle-invasive bladder cancer (MIBC). However, there is still a considerable proportion of patients who respond suboptimally to available treatments or experience adverse effects. Thus, identifying novel biomarkers to predict response to NCT of MIBC is urgently needed. Methods: A total of 23 patients were enrolled in this study, all of whom were cT2-T4aNxM0 MIBC and received 2̃4 cycles CG (gemcitabine and cisplatin) NCT. Radiographic assessment was performed at the end of each cycle or at the time of progression. Tumor tissue were collected from all patients before NCT. Whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed for tissue samples. In addition, peripheral blood was collected as a control for WES. Treatment responses were assessed by comparing the imaging data before and after treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients with CR and PR were regarded as the responder group, and those with SD and PD were regarded as the non-responder group. Results: Number of patients received 2̃4 cycles NCT were 16 for the responder group and 7 for the non-responder group. Of 19 patients completed WES, 13 patients achieved response and 6 patients did not respond. In the responder group, 6 patients (46%) had variant in any of RB1, ERCC2 and ATM, which were previously reported to predict better response to NCT. Only a patient (16.7%) in the non-responder group had any of those variants. Additionally, our results showed that 3 patients in the non-responder group had MAST4 gene mutations, but not in the responder group, and there was a significant difference between the two groups (p &lt; 0.05). There were no differences in Tumor Mutational Burden (TMB) and Microsatellite instability (MSI) between the two groups. RNA-seq was also completed in 18 patients, of which 14 patients achieved response and 4 patients did not respond. Significant differences in gene expression (eg. UPK3A, CD8B2, TUBB2B) between the two groups were found. The KEGG pathway enrichment analysis revealed that down-regulated DEGs were enriched in the Cytokine-cytokine receptor interaction pathway and up-regulated DEGs were enriched in the Steroid hormone biosynthesis. The infiltration of immune cells in the non-responder group was higher, and the CD4 cells, B cells, Th17 cells, and NK cells in the non-response group were significantly higher than those in the responder group (p &lt; 0.05). Conclusions: Patients with MAST4 mutations may be insensitive to GC NCT. The non-response group had higher levels of immune cell infiltration and may be more sensitive to immunotherapy. These results require further validation in additional sample sets.
Public health surveillance in countries hosting displaced people from Ukraine
Authors: Julien Beauté, Piotr Kramarz
Journal: Eurosurveillance (2022)

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Brain metastases in ovarian cancer: Association of outcomes with timing of diagnosis.
Authors: Hadi Erfani, Mudgett Mudgett, Abigail Peterson, Benjamin Seidman, Farr Nezhat, Tanja Pejovic
Journal: Journal of Clinical Oncology (2022)

e17565 Background: Brain metastases (BM) in ovarian cancer (OC) are rare and late events during the disease course. We report our data on patients with OC who developed BM and compared the outcomes with subjects with evidence of BM at the time of diagnosis from the Surveillance, Epidemiologic, and End Results (SEER) national database. Methods: Retrospective chart review of all patients with brain metastasis in the setting of previously diagnosed ovarian cancer was performed in single NCI designated comprehensive cancer institute. Inclusion criteria were: primary cancer documented as ovarian or tubal, evidence of BM, treatment and follow up information. For comparison and due to rare nature of ovarian cancer cases with BM we utilized the SEER database. SEER data base reports only on patients with OC who had BM at the time of diagnosis. Study groups were: 1- BM at diagnosis 2- BM during disease course. Primary outcomes were overall death, and overall survival (OS) months. Secondary outcome was survival months after diagnosis of BM. Variables are reported as median and interquartile range (IQR) or number (%). Mean survival was calculated using Kaplan Meier analysis and Mantel-Cox rank test. Cox regression analysis was performed to calculate adjusted hazard ratios (HR). Results: 106 and 24 subjects were included with evidence of BM at diagnosis (Group 1, 2010-2016, SEER database) and during the disease (Group2, 1992-2017, institutional data), respectively. Age at diagnosis of OC was significantly higher in group 1 (64 year vs. 55 year, p = 0.002). In group 2, BM were diagnosed at median interval of 33.5 months. The median OS month was 3 [1, 10] months and 58 [21, 122] in group 1 and 2, respectively (p &lt; 0.001). Although overall mortality rate was not statistically significantly different between the study groups, survival months after diagnosis of BM in group 2 was significantly higher than group 1 (14 months [4, 32] versus 3 months [1, 10], p = 0.002). Cox-regression analysis revealed 58% decrease in the hazard of overall death when the BM is diagnosed during the disease course. (Adjusted HR = 0.42, 95% CI: 0.19-0.91, p = 0.03). Conclusions: Outcomes of OC with BM is poor with high mortality rate regardless of timing of diagnosis of BM. Our study revealed that patients with diagnosis of BM during the disease course have statistically significantly longer survival after diagnosis of BM compared to those with BM at the time of diagnosis. In order to understand the occurrence of BM in OC and these differences, it is necessary to gain knowledge in the genetic and immune mechanisms that drive and allow the development of BM in ovarian cancer. This will allow for development of effective therapeutic strategies to treat BM, which is of critical importance now as we are gaining better control of peripheral disease in women with ovarian cancer.
Changes of immune microenvironment before and after chemoradiotherapy in cervical cancer.
Authors: Sihan Liu, Qianru He, Xiaodan Xing, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e17503 Background: Cervical cancer is the fourth most common cancer in women worldwide. Metastasis and invasion of cervical cancer are closely related to the tumor microenvironment. As an effective treatment, chemoradiotherapy plays a vital role in immune-related cells and factors. However, little is known about the effect of chemoradiotherapy on the immune microenvironment in cervical cancers. Therefore, we studied the immune microenvironment alterations before and after chemoradiotherapy and analyzed their prognostic significance in cervical cancer patients. Methods: We recruited 15 patients with stage IB1-IVA cervical squamous cell carcinoma. Pelvic intensity-modulated radiotherapy (IMRT) was performed with conventional segmentation of 2Gy per irradiation (IB3 stage was treated with synchronous cisplatin for weeks), FFPE samples pre-treatment, and one-week after-chemoradiotherapy were conducted an exploratory biomarker analysis based on gene expression profiling (GEP). The panel of 289 genes was customized based on critical genes and pathways during tumor immunoregulation (e.g., tumor antigen release, T cell activation, and immune metabolism). The differential expressed genes between these two groups were then assessed. Results: Forty-two genes were found to be differentially expressed, with 21 genes having &gt; 1.5-fold mean expression difference after chemoradiotherapy. Analysis of important GO terms and KEGG pathways indicated that the pathways enriched by different genes are located in immune-related pathways, specifically, T cell activation (GO-BP), cytokine activity (GO-MF), and cytokine-cytokine receptor interaction (KEGG). After-chemoradiotherapy, the enrichment of tumor-infiltrating lymphocytes (TILs) varied greatly, especially the macrophages. Conclusions: This study preliminarily demonstrated that chemoradiotherapy caused the release of pro-inflammatory like CCR7 and CD69 and immune cell (macrophages) infiltration alterations after chemoradiotherapy in cervical cancer patients.
HGG-56. Spatial mapping of the tumor micro-environment in pediatric glioma
Authors: Julie Messiaen, Asier Antoranz, Yannick Van Herck, Ben Verhaaren, Pouya Nazari, Ivey Sebastian, Giorgia Milli, Francesca Bosisio, Jon Pey, Isabelle Vanden Bempt, Raf Sciot, Sandra Jacobs, Frederik De Smet
Journal: Neuro-Oncology (2022)

Abstract High-grade glioma are the main cause of cancer-related death in children. The highly heterogeneous composition of the tumor cells and their interactions with the tumor micro-environment (TME), contribute substantially to the poor response to treatment and the high levels of morbidity and mortality. Here, we used high-dimensional, multiplexed immunohistochemistry to map the single-cell tissue architecture of 26 pediatric glioma samples covering 8 histologic diagnoses, allowing us to determine the spatial distribution of the various tumoral subtypes and how these interact with their local immune-microenvironment. Overall, this analysis showed that tumor grade anti-correlated with the amount of infiltrating cytotoxic T-lymphocytes (CTLs), which were typically more exhausted in the higher grade tumors. In addition, tumor associated macrophages were primarily infiltrating from the blood and presented an M2-like anti-inflammatory phenotype which became more extended with tumor grade. Using the spatial information, possible cell-cell interactions could be determined. In lower grade glioma, we observed an increased activation level of CTLs that were closely located to neighboring T-helper cells. In pediatric glioblastoma, on the other hand, CTLs, even though they were located close to a T-helper cell, could only minimally be activated, and showed more extended exhaustion when residing further away. Additionally, the activation of the CTLs was associated to the distance to the closest PD-L1 positive macrophage in pilocytic astrocytoma and desmoplastic infantile ganglioglioma. In conclusion, with the use of multiplex immunohistochemistry, we are able to study the tumor and TME of pediatric glioma in depth on a single-cell and spatial level, which allows us to further study the heterogeneous landscape of these tumors.
HGG-35. Radiation Induced High Grade Gliomas: A Single Center Experience
Authors: Mrinal Joshirao, Sameer Farouk Sait, Nancy Bouvier, Katherine Hill, Yasmin Khakoo, Kim Kramer, Stephen Gilheeney, Suzanne Wolden, Craig Nolan, Lauren Schaff, Marc Rosenblum, Tejus A Bale, Jonathan T Yang, Andrew Lin, Ira J Dunkel, Matthias Karajannis
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Patients receiving cranial radiotherapy (RT) are at risk for a subsequent radiation-induced glioma (RIG). RIGs are rare, generally develop with a latency of 2 years to several decades, display high-grade histology and an aggressive clinical course with poor prognosis. METHODS: We retrospectively analyzed patients with a diagnosis of RIG seen at our institution from 2001-2021, analyzing clinical, histological, molecular, and genetic characteristics. RESULTS: Twenty-one patients (n=15 male) with a history of ALL (n=6), medulloblastoma (n=5), germ cell tumors (n=4), or other (n=6) diagnosed at a median age of 8.3 years (range 1.6 to 36.4) were identified. Median age at RIG diagnosis was 18 years (range 7.8 to 66.9). Prior RT was focal+craniospinal (n=7), whole brain (n=5), total body (n=3), focal (n=1), or unknown (n=5). Median radiation dose received was 2,340 cGy (range 1,200 to 5,400). The median time from RT to RIG diagnosis was 7.7 years (range 1.6 to 23.8). All RIGs were histologically high grade (WHO Grade III or IV). Immunohistochemistry did not reveal IDH(R132H) (n=9) or H3K27M (n=8) in any tumor. Some tumors demonstrated loss of expression of ATRX (1/9) and/or H3K27me3 (3/6), and/or strong diffuse expression of p53 (0/3). Targeted panel sequencing (n=10) revealed recurrent somatic alterations including CDKN2A/B, PDGFRa/KIT/KDR, TEK, MTAP, ATM and NF1. Germline alterations were detected in 4/12 patients (pathogenetic variants in ATM, CHEK2, HOXB13 and NF1). With median follow-up of 4.5 years, two-year PFS and OS for the cohort (n=20) were 10% and 44% respectively. Two patients (with anaplastic oligodendroglioma and anaplastic astrocytoma) are alive without progression 5.4 and 13.6 years after diagnosis following surgery, RT and chemotherapy. CONCLUSION: Although RIGs are associated with a poor prognosis, they are not always fatal. Our findings suggest aggressive therapy should be considered for these patients.
Genomic characterization of immune checkpoint inhibitor resistance genes and hyperprogression genes in advanced solid tumors.
Authors: Libin Xu, Ge Zhang, Tianhao Mu, Zhizheng Wang
Journal: Journal of Clinical Oncology (2022)

e14582 Background: Immune checkpoint inhibitors have been widely used in the systematic treatment of various advanced solid tumors, but they show poor efficacy or lead to hyperprogression in some patients. Some studies reported that EGFR mutations, ALK fusion, interferon pathway or Wnt signal pathway gene mutations might reduce the efficacy of immunotherapy and lead to tumor hyperprogression. The aim of this study was to determine the frequency of gene variations associated with immunotherapy resistance or hyperprogression in advanced solid tumors. Methods: The tumor tissues or blood samples of 111 patients with advanced solid tumors were collected. The tumor tissues were sequenced by targeted next-generation sequencing (55 genes, Illumina novaseq 6000), MSI (PCR) and PD-L1 detection (IHC). Blood cfdna was extracted and sequenced by targeted next-generation sequencing (55 genes, Illumina novaseq 6000). Results: A total of 111 patients with advanced solid tumors were included in the study, including 34 patients with colorectal cancer, 27 patients with hepatobiliary tumors, 18 patients with gastric cancer, 15 patients with urothelial carcinoma, and 17 patients with other solid tumors. Among the 82 samples tested for MSI, there were 77 cases of MSS (93.9%), 1 case of MSI-L (1.2%), and 4 cases of MSI-H (4.9%). 44 samples were tested for PD-L1 expression. 33 (75%) had PD-L1 expression &lt; 1%, and 11 (25%) had PD-L1 expression greater than 1% but less than 49%. Among the genes related to immunotherapy, the mutations of genes related to cell growth or cell cycle regulation (EGFR, ALK, CDKN2A and CCND1) accounted for 3 (2.7%), 5 (4.5%), 12 (10.8%) and 5 (4.5%), respectively. The mutation of antigen presentation related gene (B2M) accounted for 3 (2.7%). The mutations of interferon signaling pathway related genes (JAK1, JAK2, JAK3 and IFNGR1) accounted for 2 (1.8%), 5 (4.5%), 1 (0.9%) and 1 (0.9%), respectively. The mutations in Wnt signaling pathway related genes (APC, AXIN1, CTNNB1) accounted for 41 (36.9%), 5 (4.5%) and 7 (6.3%). The mutations of tumor suppressor genes (PTEN, STK11 and PTPN2) accounted for 9 (8.1%), 1 (0.9%) and 3 (2.7%). Mutations in other genes (APLNR, DNMT3a, MDM2) accounted for 1 (0.9%), 6 (5.4%) and 7 (6.3%). Conclusions: Our study shows that in patients with advanced solid tumors, there are multiple gene variants related to drug resistance or hyperprogression of tumor immune checkpoint inhibitor treatment, suggesting that it may be the reason for the difference in the efficacy of immunotherapy. It is necessary to further study the efficacy of immunotherapy in patients with different gene mutations and the combination of immune checkpoint inhibitors for patients with different pathway mutations.
Peri- and postoperative outcomes of salvage robot-assisted radical prostatectomy in prostate cancer patients: A high-volume center experience
Authors: J.H. Witt, N. Liakos, C. Wagner, A. Schuette, M. Mendrek, T. Karagiotis, L. Esch, M. Oelke, S-R. Leyh-Bannurah
Journal: European Urology (2022)
Outcomes of importance to men with advanced prostate cancer: PIONEER interview study
Authors: S. Tripathee, J. Healey, K. Beyer, L.D. Venderbos, M. Van Hemelrijck, M.J. Roobol, J. Huber, E.J. Smith, M. Imran Omar, J. N'Dow, S.J. Maclennan, S. Maclennan
Journal: European Urology (2022)
ETMR-11. Transcriptional changes upon knockdown of altered<i>BCOR/BCORL1</i> transcripts in preclinical models of CNS embryonal tumors with BCOR-related alterations
Authors: Martin Piontek, Dominik Kirchhofer, Lisa Gabler, Daniela Lötsch-Gojo, Christine Pirker, Felix Schmitt-Hoffner, Carola N Jaunecker, Marcel Kool, Walter Berger, Johannes Gojo
Journal: Neuro-Oncology (2022)

Abstract BCL-6 transcriptional corepressor (BCOR) is an epigenetic regulator that silences gene expression mainly via the polycomb repressive complex 1.1 (PRC1.1). BCOR genomic alterations are found in a variety of different tumors and recently central nervous system (CNS) tumors with BCOR internal tandem duplication (ITD) were classified as a distinct molecular subgroup. We established and characterized two cell models derived from BCOR altered CNS tumor patients. One model is characterized by a frameshift mutation in the BCOR gene resulting in the expression of a truncated protein lacking the C-terminal PUFD domain required for correct assembly of the PRC1.1. Additionally, this model harbors a translocation of the BCOR homologue BCORL1. The second model has a characteristic internal tandem duplication (ITD) within the BCOR gene. To study the effects of mutated BCOR/BCORL1 on gene expression, we performed siRNA mediated knockdown of altered BCOR/BCORL1 transcripts in both models and analyzed transcriptional changes by mRNA expression array. Differentially expressed genes in BCOR/BCORL1 knockdown versus wild type conditions were enriched for signaling pathways involved in cell cycle progression, cell growth, DNA replication and cancer. This suggests that the alterations in BCOR/BCORL1 might have pro-oncogenic effects and thereby contribute to the aggressive phenotype of this disease. Especially in the BCOR ITD model knockdown of BCOR led to transcriptional downregulation of genes associated with the development of brain tumors such as FGF18, PDGFA and PDGFRA. Our results indicate that specific BCOR/BCORL1 alterations might impair its endogenous function as transcriptional repressor and deregulate the expression of multiple PRC1.1 target genes. An in depth characterization of epigenetic and transcriptional changes in BCOR/BCORL1 altered CNS tumors could lead to the identification of critical downstream effectors and ultimately reveal new therapeutic vulnerabilities.
Covid-19 and mRNA technology are helping Africa fix its vaccine problems
Authors: Emma Bryce, Sandy Ong
Journal: BMJ (2022)

After the disastrous effect of vaccine nationalism on access in Africa, boosting local production is key to preventing a repeat in future pandemics. WHO's new mRNA vaccine hub is at the forefront, report <b>Emma Bryce</b> and <b>Sandy Ong</b>
Management of neurofibromatosis type 1-associated plexiform neurofibromas
Authors: Michael J Fisher, Jaishri O Blakeley, Brian D Weiss, Eva Dombi, Shivani Ahlawat, Srivandana Akshintala, Allan J Belzberg, Miriam Bornhorst, Miriam A Bredella, Wenli Cai, Rosalie E Ferner, Andrea M Gross, Gordon J Harris, Robert Listernick, Ina Ly, Staci Martin, Victor F Mautner, Johannes M Salamon, Kilian E Salerno, Robert J Spinner, Verena Staedtke, Nicole J Ullrich, Meena Upadhyaya, Pamela L Wolters, Kaleb Yohay, Brigitte C Widemann
Journal: Neuro-Oncology (2022)

Abstract Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multidisciplinary NF1 experts.
National claims data analysis of outcomes of hospitalized cancer patients without COVID-19 infection during versus prior to the COVID-19 pandemic.
Authors: Jennifer Lee Caswell-Jin, Maryam Nemati Shafaee, Mina Liu, Lan Xiao, Esther M John, Melissa Bondy, Allison W. Kurian
Journal: Journal of Clinical Oncology (2022)

e18679 Background: There has been growing concern regarding the impact of the COVID-19 pandemic on health care delivery and disruption of care to cancer patients. Reductions in cancer surgeries, delays in administration of life saving chemo and radiation therapies, and lower rates of cancer-related hospitalizations have been reported. While cancer patients with COVID-19 infection have poor hospitalization outcomes, less is known about the outcomes of hospitalized cancer patients without the infection. This study aimed to describe the impact of the COVID-19 pandemic on outcomes of the most common cancer-related hospital admissions for patients without COVID-19 infection at a national level using insurance claims. Given the concern for disruptions in their care, we hypothesized that hospitalized cancer patients may have worse outcomes. Methods: We used the Optum Clinformatics Data Mart, consisting of claims records linked to electronic health records, including an average of 8 million adult Americans per year enrolled for at least 6 months. We identified cancer-related hospitalizations from 02/2018-05/2021 and included patients with at least of one of these cancer types: breast, prostate, bladder, ovarian, cervical, lung, colorectal, esophageal, liver, small intestine, gastric, or gallbladder cancer. Patients with cancer-related hospitalization who had COVID-19 infection were excluded. The main outcome was “severe adverse outcome” and included at least one of the following: mortality during or within 30 days of hospitalization, mechanical ventilation during hospitalization, intensive care unit admission, or discharge to hospice. We used Poisson regression to compare the number of hospitalizations before (2/1/2018-1/30/2020) and during (2/1/2020-5/30/2021) the pandemic and a Chi-squared test to compare the proportion of cancer-related hospitalizations with severe adverse outcomes over that time period in 4-month intervals and across cancer types, gender, (male vs female) and geography (the 9 Census Bureau regions). Results: There were 82,796 cancer-related hospitalizations in the period 2/2018-05/2021. A slightly higher proportion of cancer-related hospitalizations resulted in a severe adverse outcome during the pandemic as compared to prior to the pandemic (41.8% vs 40.9%; p = 0.012). There were no differences by cancer site, gender, or geography. The number of hospitalizations was lower during vs prior to the pandemic (p &lt; 0.0001). Conclusions: The number of cancer-related hospitalizations during the pandemic was lower compared to before the, and a slightly higher proportion of those hospitalized experienced severe adverse outcomes among insured U.S. cancer patients without COVID-19 infection. The lower number of cancer-related hospitalizations during the pandemic warrants further investigation.